1. Field of the Invention
The present invention relates to oral controlled release dosage formulations containing a beta-adrenergic blocking agent. More specifically, the present invention relates to an oral dosage formulation in the form of a capsule containing pellets comprising a beta-adrenergic blocking agents, such as propranolol, atenolol, metoprolol, acebutolol, nadolol, sotalol, bisoprolol, penbutolol, timolol, betaxolol, labetalol, pindolol, carteolol, esmolol or their pharmaceutically acceptable derivatives, salts and stereoisomers. Most preferably the beta-adrenergic blocking agent is propranolol hydrochloride.
2. Description of the Prior Art
Beta-adrenergic blocking agents such as propranolol [(1-(isopropylamino)-3-(1-naphthyloxy)-2 propranolol] inhibit response to adrenergic stimuli by competitively blocking beta-adrenergic receptors within the myocardium and within bronchial and vascular smooth muscle. Propranolol decreases heart rate and prevents exercise-induced increases in heart rate, decreases myocardial contractility, decreases cardiac output, increases systolic ejection time, and increases cardiac volume. The drug also decreases conduction velocity through the sinoatrial (SA) and atrioventricular (AV) nodes and decreases myocardial automaticity via beta-adrenergic blockade. These compounds are useful in the management of angina to reduce the frequency of anginal attacks, allow a decrease in nitrate dosage, and increase the patient's exercise tolerance.
Currently, propranolol is used for the management of various cardiac arrhythmias and as monotherapy or in combination with other classes of antihypertensive agents for management of hypertension. Other uses include migraine prophylaxis, essential tremor, secondary prevention of myocardial infarction, reduction in the risk of cardiovascular mortality in patients who have survived the acute phase of myocardial infarction, hypertrophic subaortic stenosis, pheochromocytoma, thyrotoxicosis, and anxiety. Propranolol has been used in the management of cyanotic spells of Fallot's tetralogy, bleeding in patients with cirrhosis, acute exacerbations of schizophrenia, and tremors associated with lithium therapy.
Propranolol is a biopharmaceutical class I agent that is freely soluble in water with a high permeability characterized by rapid and almost complete absorption following oral administration. A major drawback of oral propranolol is extensive metabolism so that only a small proportion reaches the systemic circulation. Peak plasma concentrations occur 60–90 minutes after oral administration of the conventional tablets, necessitating administration three or four times daily. A sustained release form of propranolol for once daily administration is available and is marketed by the Wyeth-Ayerst Company under the trade name INDERAL® LA.
Sustained release tablet or capsule forms of propranolol comprising coated propranolol HCL pellets are described in U.S. Pat. Nos. 5,968,554, 4,898,737, 4,248,856, 4,248,857, 4,248,848, 4,309,404, 4,309,405, 4,309,406, 4,728,512, 4,780,318 and spheroids made from propranolol in admixture with microcrystalline cellulose are described in U.S. Pat. No. 4,138,475. The present invention relates to a new sustained release pharmaceutical composition made of sugar spheres which is not disclosed in, nor rendered obvious by, said patents nor elsewhere in the art.
Numerous techniques are in the prior art for preparing sustained or controlled release pharmaceutical formulations. One common technique involves surrounding an osmotically active drug core with a semipermeable membrane. The drug is released from the core over time by allowing a fluid such as gastric or intestinal fluid to permeate the coating membrane and dissolve the drug so the dissolved drug can permeate the membrane. In some cases a hydrogel is employed to push the active ingredient through the passageway in the membrane.
Another common technique for preparing controlled release pharmaceutical formulations is to encapsulate a plurality of beads, pellets or tablets that are coated with varying levels of a diffusion barrier and/or different types of the diffusion barriers. Release of the pharmaceutical may occur by leaching, erosion, rupture, diffusion or similar actions depending on the nature and thickness of the coating material. These products require multi-layered coating, sometimes as much as 30 to 90 coats.
Film coating techniques are characterized by the deposition of a uniform film onto the surface of a substrate. Because of the capability of depositing a variety of coating materials onto solid cores, this process has been used to make controlled release dosage forms starting from different formulations, such as tablets, granules, pellets and capsules. Cores are usually prepared using one of the following processes: compaction, surface-layering, agglomeration or extrusion-spheronization.
The current surface-layering technique for pelletization involves the use of inert substrates and their enlargement by intermittently spraying a binder solution and applying the active substance powder in a rotating coating pan or in a fluidized bed. This current procedure still presents drawbacks. The powder layering process requires a great deal of repetition of wetting and powdering operations and is thus time consuming. Undesired agglomeration such as the formation of seedless drug agglomerates of various sizes and adhesion of the pellets to the wall of the coating equipment can occur producing a high loss of drug. Additionally, the powder layering technique requires specialized equipment such as a rotary-tangential fluidized bed or modified rotating pans. To this end, the present invention relates to a pelletization process, typified by the application of a beta-adrenergic-blocking agent/water insoluble binder solution to an inert core followed by application of a sustained release coating. It is an object of the present invention to provide a controlled or sustained release dosage formulation for beta-adrenergic blocking agents, preferably propranolol, or its pharmaceutically acceptable salt, that is easy to manufacture and can be used to prepare a range of dosing levels suitable for once daily administration.
It is a further object of the present invention to provide a controlled or sustained release dosage form for beta-adrenergic blocking agents, preferably propranolol, or its pharmaceutically acceptable salt, characterized by a high extent of absorption, which is largely invariable from individual to individual, and hence by a high bioavailability that can provide therapeutic levels of the drug to an animal or human in need of such treatment over a twelve to twenty-four hour period.